OPIOID ANALGESICS presentation11345.pptx

DEPARTMENT OF PHARMACOLOGY
ALGESIA :
An unpleasant bodily sensation perceived as suffering, usually evoked
by an external or internal noxious stimulus.
ANALGESIC :
A drug that selectively relieves pain by acting in the CNS or on
peripheral pain mechanisms, without significantly altering
consciousness.
Excessive pain can cause :
• Sinking sensation
• Apprehension
• Sweating
• Nausea
• Palpitation
• Rise or fall in blood pressure
• Tachypnoea. 2

Types of pain :
 SOMATIC PAIN :
Pain arising from the skin or integumental structures likes
muscles, bones and joints.
 VISCERAL PAIN :
Pain arising from the viscera is vague dull aching type difficult to
pinpoint to a site.
 REFERRED PAIN :
When pain referred to a cutaneous area which receives nerve
supply from the same spinal segment as that of the affected
viscera.
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ANALGESICS:
Opioid analgesics / morphine like – analgesics
Nonopioid / non narcotic / aspirin – like /
antipyretic or anti-inflammatory analgesics.
Adjuvant analgesics: Anticonvulsants : Gabapentin /
pregabalin, Carbamazepine Antidepressants –
Amitriptyline.
4

Opium –
• Eber’s papyrus
SERTURNER a pharmacist isolated the active principle –
Morphine in 1806.
Named after Greek god of dreams – Morpheus.
Derived from the poppy capsule – Papaver somniferous
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CLASSIFICATION :
 Agonists :
Natural opium alkaloids :
Morphine, Codeine
Semi-synthetic opioids:
Diacetylmorphine, Pholcodine, Ethylmorphine
Synthetic opioids :
Pethidine (Meperidine), Fentanyl, Remifentanil,Tapentadol,
Tramadol
 Antagonists :
Naloxone, Naltrexone, Nalmefene, Alvimopan
 Mixed agonist – antagonists:
Pentazocine, Nalbuphine, Butorphanol, Buprenorphine,
Nalorphine 6

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Antitussives:
Dextromethorphan, Codeine
Anti-diarrheal:
Loperamide, Diphenoxylate

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ENDOGENOUS OPIOID PEPTIDES
• Beta – Endorphins – Proopiomelanocortin (POMC)
• Enkephalins -Pro enkephalin
• Dynorphins – A and B
• Nociceptin / Orphanin.
• Endomorphins 1 and 2
• Secreted naturally by the body for pain response.

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OPIOID RECEPTORS
Mu(µ) - MOR
1 , 2
Kappa( )- KOR
𝜿
1,2
Delta ( )- DOR
𝝳
1,2,3
• Analgesia (spinal
& supraspinal
level)
• Euphoria
• Miosis
• Sedation
• Dependence
• Respiratory
depression
• Inhibits GIT
motility
& supraspinal)
• Dysphoria
• Dependence
• Respiratory
depression
• Psychotomimetic
effect
• Miosis
& supraspinal)
• Respiratory
depression
• Proconvulsant
action
• Affective behavior
• Reinforcing
actions
• Reduced GI
motility

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NOR – Nociceptin opioid receptor
Drug reward and reinforcement, stress responsiveness,
learning and memory.
Note:
Opioid receptors - also present – Peripheral nerves –
respond to peripherally applied opioids and locally released
endogenous peptides during inflammation.

15
Pathway of reward :
µ receptors are situated on GABAnergic neurons in CNS.
Connected to various dopaminergic neurons in CNS.
Opioids – blocks release of GABA
GABA mediated inhibition is reduced
Leads to increase dopaminergic outflow in ventral pallidum
Positive reinforcing state – Enhance reward

SYSTEMIC EFFECTS OF OPIOID ANALGESICS
Central nervous system effects
1)Analgesia :
Mainly through Mu(µ) - µ1 and µ2 receptors
Raises the pain threshold.
Perception of pain and reaction to it are altered.
Dull aching pain is better reduced rather than sharp
pricking pain.
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2) Euphoria :
Floating sensation with decreased anxiety and distress.
Produces a warm flushing of the skin and immensely
pleasurable sensation lasting for about 45 seconds which
is known as Kick or Rush .
Mediated through Mu 1 receptors.
3)Sedation and Hypnosis :
Drowsiness.
Morphine disrupts normal REM and non REM sleep
patterns.
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4)Respiratory depression –
Depress the medullary centers that regulate
the rate of respiration.
It may alter the rhythm to produce irregular and periodic
breathing.
 Commonest cause of death in acute opioid
poisoning.
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5)Cough suppression – Antitussive
 Suppression of cough reflex.
 May allow accumulation of secretions.
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6) Miosis :
(Constriction of the pupil)
 3rd
cranial nerve (oculomotor ) stimulation(µ and k
receptors)
 Pin point pupil – important diagnostic sign in
opioid toxicity.
20

7) Truncal rigidity
Intensification of tone in the large trunk muscles.
Reduces thoracic compliance and interferes
with ventilation.
21

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8) Nausea and vomiting
oCTZ stimulation in the brain stem.
9)Temperature
oDepression of hypothalamic thermostatic center –
results in hypothermia occurs in cold surroundings.
10)Convulsion
oHigh doses – increases the excitability of neurons –
morphine -3-glucuronide.

PERIPHERAL EFFECTS
1)Cardiovascular system
 Most opioids cause bradycardia and hypotension by
depression of vasomotor centre, histamine release and
directly acting on blood vessels – dilatation.
 Meperidine causes tachycardia (due to structural
similarity to atropine).
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2) Gastrointestinal tract
 Motility is decreased and increased tone in the stomach.
 Decreased secretion of hydrochloric acid.
 Delay in the passage of fecal matter and
increased absorption of water in the large
intestine.
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3) Biliary Tract
Contraction of biliary smooth muscle.
Constriction of sphincter
of Oddi - intrabiliary pressure.
25

4) Genitourinary system
Decreases renal plasma flow.
Increases renal tubular sodium reabsorption.
Increases ureteral and bladder tone.
Increases sphincter tone.
Inhibits voiding reflex.
Results in urinary retention especially in elderly.
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5) Uterus
It may prolongs labor.
6)Neuroendocrine
Stimulates release of ADH , Prolactin and Somatotropin
but inhibits release of LH, FSH and ACTH.
Addicts – suffer from impotence, loss of libido and
infertility.
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7)Pruritus :
Flushing of the skin
accompanied by sweating and itching – dilatation of
cutaneous blood vessels.
8) Immune system :
Mild immunosuppressant action

PHARMACOKINETICS :
 Given orally absorption – slow.
 Undergoes extensive first pass metabolism.
 Bioavailability – 20 to 40%.
 Rectal routes or highly lipid soluble preparations
are available.
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 Given subcutaneously onset of action is in 15
to 20 mins, Duration : 3-5 hours.
 Metabolized by glucuronide conjugation.
 Morphine-6 –glucuronide – More potent.
 Morphine undergoes enterohepatic
circulation.
 Morphine crosses blood brain and placental
barrier
 Dose reduction is required in renal disease
patients.
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ADVERSE EFFECTS :
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 Apnea in the newborn
 Allergic reactions

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MCQ:
Which among the following metabolite of Morphine
is responsible for CNS excitability action?
a. Morphine 6 glucuronide
b.Morphine 3 glucuronide
c. Morphine 6 sulphate
d.Morphine 3 sulphate

33
Tolerance
 Continued use of opioid analgesics.
 Dose has to be increased to achieve the same analgesic
effect.
 Marked tolerance develops to the analgesic, sedating,
respiratory depressant, antidiuretic, emetic and
hypotensive effects.

But not to miotic , convulsant and constipating actions.
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DEPENDENCE
Physiological state of neuroadaptation
resulting from repeated administration of
the drug
1)Psychological :
- Drug seeking behavior.
- Tolerance may or may not be present.
- Withdrawal effects are less frequent.

2) Physical:
- Intense drug craving.
- Tolerance is present.
- Severe withdrawal effects ( pain, hyperventilation, coughing,
mydriasis, hypertension, diarrhea, agitation and
piloerection)
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Withdrawal symptoms:
 Irritability
 Body shakes
 Jumping
 Yawning
 Lacrimation
 Sweating
 Diarrhoea
 Palpitation
 Insomnia
 Rise in BP
 Loss of weight
 Piloerection – Cold turkey

ACUTE MORPHINE POISONING :
Accidental, suicidal or homicidal.
Lethal dose – 250mg.
SIGNS :
• Respiratory depression with shallow breathing
• Pin point pupils
• Hypotension
• Shock
• Cyanosis
• Flaccidity
• Stupor
• Hypothermia
• Coma
• Death due to respiratory failure and pulmonary edema.
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TREATMENT :
A- Airway, B- Breathing, C- circulation
• Positive pressure ventilation.
• Maintenance of BP
• Gastric lavage with potassium permanganate to remove
unabsorbed drug.
• Specific antidote is Naloxone – 0.4 -0.8mg IV repeated till
respiration becomes normal.
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TREATMENT OF DEPENDENCE:
 Hospitalization of the patient.
 Gradual withdrawal of morphine.
 Substitution therapy – Methadone
(1mg Methadone = 4mg Morphine).
 Naltrexone
 Clonidine
 Diazepam, Psychotherapy, Occupational therapy and
rehabilitation.

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MORPHINE
 Extensive first pass
metabolism.
 Routes – Oral, I.V. , I.M. or SC.

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 Uses:
 As analgesic:
 In Myocardial infarction to relieve pain, pain in the patients
having cancers of higher stages.
 Neurogenic shock due to severe pain- crush injuries.
 Cancer pains.
 Epidural analgesia – Morphine ( Fentanyl > Morphine)
 Patient controlled analgesia (PCA)
 Preanesthetic medication
 Acute left ventricular failure / acute pulmonary edema.

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CONTRAINDICATIONS OF MORPHINE:
1. Head injury
2. Bronchial asthma
3. Chronic obstructive pulmonary disease
4. Hypotension.
5. Hypothyroidism
6. Infants and elderly
7. Hypertrophy of prostate
8. Biliary spasm.
9. Pregnancy
10. Unstable personality

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C O D E I N E
- It is methyl-morphine, occurring naturally in opium.
- 1/10th
of analgesic potency of morphine.
- Depresses the cough centre in sub analgesic doses.

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C O D E I N E
- Produces less respiratory depression.
- Given orally.
- Partial mu agonist, when used as analgesic in high
doses, produce constipation.
- Used as antitussive.

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- Synthetic opioid.
- Long acting mu receptor agonist and also blocks NMDA
receptors.
- Effective by oral route.
- Euphoric effects are less so abuse potency is less.
- Associated with prolonged QT syndrome.
METHADONE

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Uses of Methadone:
 Relief of chronic pain.
 Treatment of opioid abstinence syndromes.
 Treatment of heroin users – replacement modality to treat
heroin dependence.

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• Plasma half life : 1-6hrs.
• 100 times more potent than morphine, given IV, intrathecal, epidural.
• Exhibit a short duration
• There is minimal depressant effect on the heart.
• Doesn’t increase intracranial pressure
Uses
 Anesthetic adjuvants
 Post operative pain – Transdermal patch
 Cancer pain
 Used as a component in neurolept analgesia.
FENTANYL

- 1/10th
as potent as morphine.
- Potent mu agonist.
- Rapid onset of action but of short duration.
Uses –
Preanesthetic and obstetric analgesia
Adverse effects -
Atropine like effects(dry mouth, blurred vision,tachycardia).
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PETHIDINE (MEPERIDINE)

• Centrally acting analgesic.
• Weak mu opioid receptor activity.
• Inhibits neuronal uptake of NA and seratonin, thus
increases 5HT release and activates monoaminergic spinal
inhibition of pain.
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TRAMADOL :

• Metabolized in liver and excreted through kidneys –
plasma t1/2 – 6 hours.
• Given orally for mild to moderate pain like in diagnostic
procedure, injury, for chronic cancer pain.
• Adverse effects :
• High incidence of nausea and dizziness.
• Dryness of mouth, sedation.
• May precipitate seizures.
• Seratonin syndrome.
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TRAMADOL :

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MIXED AGONIST - ANTAGONISTS
Buprenorphine :
- mu partial agonist
- 25-50 times more potent than morphine
 Sublingual - analgesia in post
operative patients
 Treatment of opioid addiction - initiate with a
sublingual drug followed by maintenance
therapy with fixed dose combination
formulation of buprenorphine and naloxone.

Butorphanol :
Kappa agonist and mu antagonist
Best suited for relief of acute pain
Nasal formulation – relief of migraine pain
Side effects – Drowsiness,Weakness, Sweating ,
Feelings of floating and Nausea
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Pentazocine :
 Kappa agonist with weak mu antagonist or
partial agonist properties
 Oldest mixed agent
 Oral as well as injection.
 Post-op pain, burns, trauma and cancer pain.

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OPIOID ANTAGONISTS
Naloxone:
- Competitive antagonists at mu, delta and k receptors.
- Increases respiratory rate and BP.
- Reverses sedation and dysphoria.
- “Overshoot phenomenon”.

USES :
• Morphine over dosage (0.8 to 2mg I.M./ S.C.–very
2 to 3 mins to a total of 10mg max).
• Reverse neonatal asphyxia due to opioids used in
labor.
• Diagnosis of opioid dependence – Higher doses of
Naloxone will precipitate a withdrawal syndrome in
opioid dependent patients.
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Naltrexone – Longer acting and potent -24hrs , pure
antagonist
- No euphoric effect and does not cause physical
dependence.
- Treating heroin addiction and also to prevent re-
addiction.
- Used in relapse of heavy drinking.
- Contraindicated in hepatitis and liver failure cases.

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Nalmefene – Given by intravenous infusion.
- Onset of action is fast and longer duration of action
(10hrs).
- More potent than naltrexone.
- Used in maintenance therapy in treatment of opioid
addicts.

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Methylnaltrexone:
- Derivative of naltrexone.
- Mu receptor antagonist in GIT.
- Used in treatment of constipation due to opioids.

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Alvimopan:
- Mu receptor anatagonist.
- Does not cross BBB.
- Treatment of post operative ileus following bowel
resection surgery.
- Risk of myocardial infarction.

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MCQ:
Opioid antagonist used in the diagnosis of opioid
dependence
a. Naltrexone
b.Naloxone
c. Methylnaltrexone
d.Nalmefene

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Dextromethorphan:
- Elevates the threshold for coughing.
- 10-30mg 3-6 times daily.
- Extended release suspension approved for twice daily
administration.
ANTITUSSIVES

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Loperamide:
- Slows GI motility.
- Reduction of gastrointestinal secretion.
- Oral – poor absorption.
- Usual dosage- 4-8mg/day.
ANTIDIARRHOEAL

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It is used for short surgical procedures – especially in
poor risk patients.
It is the combination of neurolept or antipsychotic –
Droperidol (2.5mg) and opioid analgesic Fentanyl (0.05mg).
Given IV – produces sedation and intense analgesia
without loss of consciousness.
It is maintained for 30 to 40 mins .
Have rapid and short action/
NEUROLEPT ANALGESIA

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THANKYOU!!

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IMPORTANT QUESTIONS:
1.Classify opioid analgesics. Explain the
pharmacological actions, uses and adverse effects
of morphine.
2.Write a note on morphine poisoning.
3.Naloxone.
4.Enumerate opioids and mention their use.

OPIOID ANALGESICS presentation11345.pptx

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